Noxiustoxin

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3D molecular structure of noxiustoxin. PDB 1sxm EBI.jpg
3D molecular structure of noxiustoxin.

Noxiustoxin (NTX) is a toxin from the venom of the Mexican scorpion Centruroides noxius Hoffmann which block voltage-dependent potassium channels and calcium-activated potassium channels.

Contents

Synonyms NTx; NXT; NXT-1; Toxin II.11; Potassium channel toxin alpha-KTx 2.1. [1]
Organism Centruroides noxius Hoffmann (Mexican scorpion) [2]
CAS Number 85205-49-8 (143074-44-6) [3]
Protein Data Bank 1SXM [4]
UniProt ID P08815 [5]
Molar Mass 4195.06 [1]
Chemical Formula C174H286N52O54S7 [3]
Amino Acid SequenceTIINVKCTSPKQCSKPCKELYGSSAGAKCMNGKCKCYNN-NH2 (Cys7-Cys29, Cys13-Cys34, Cys17-Cys36) [1]

Sources

NTX was first purified from homogenized crude venom extract of the Mexican scorpion Centruroides noxius Hoffmann, [2] found in the Mexican state of Nayarit. [6] NTX accounts for only about 1% of the scorpion venom. [7] NTX is one of the best-studied toxic peptides from scorpion venoms. [6] It was the second purified toxin obtained from the genus Centruroides after neurotoxin II [8] and the first short peptide from scorpion venom to be reported in the literature. [9] The name for noxiustoxin was first proposed in 1982, [2] before which it was known as toxin II-11 [9]

Chemistry

NTX is a peptide consisting of 39 amino acid residues. It has a molar mass of 4195.06 and the following primary amino acid sequence: TIINVKCTSPKQCSKPCKELYGSSAGAKCMNGKCKCYNN-NH2. [1] The sequence of NTX contains no histidine, arginine, tryptophan, or phenylalanine. NTX has three disulfide bridges [2] (Cys7-Cys29, Cys13-Cys34, Cys17-Cys36) and contains an amidated C-terminus. [10] NTX is similar in sequence to the margatoxin (79% identity), the kaliotoxin (51% identity), the charybdotoxin (49% identity), and the iberiotoxin (38% identity). [10] The three-dimensional solution structure of NTX has been solved by nuclear magnetic resonance (NMR). [11]

Target

NTX blocks the pore of several types of voltage-gated K+ channels by reversibly binding to the channel receptor site. [2] Furthermore, it affects calcium-activated potassium channels of skeletal muscles. [12] In the squid axon, NTX was found to have relatively low binding affinity with their target site on the channel protein (KD = 300nM). [9]

Mode of action

NTX associates reversibly with K+ channels and thus decreases K+ permeability in brain synaptosomes. [13] The location of the active site of NTX is not completely known yet. However, it is believed to be located close to the N-Terminal portion of the toxin as administration of synthetic-nonapeptide NTX1-9, which corresponds to the N-Terminal sequences of NTX, leads to symptoms of intoxication that are very similar to native NTX, while a second synthetic active fragment, corresponding to the C-Terminal of NTX, did not lead to symptoms of intoxication. [14]

Furthermore, the mode of action of NTX is thought to be concentration dependent. K+ currents are found to be blocked by NTX at concentrations lower than 1.5 μM in a voltage-independent manner and above 1.5 μM in a voltage-dependent manner. [15] The blocking of K+ channels by NTX is never complete, which indicates that NTX is either not able to fully block a channel or that not all channels have a receptor site for NTX. [15]

Toxicity

LD50 of the venom is 0.26 μg/g in albino mice after intraperitoneal injection. [16] Intoxication symptoms of mice include hyperexcitability, lacrimation, convulsions, salivation, dyspnea, and eventually death by respiratory paralysis. [14]

Treatment

Although the venom of Centruroides noxiusHoffmann is the most toxic of all the Mexican scorpions, [17] it is less medically important, because Centruroides noxius does not cohabitate with humans [18]

Medical significance

It is suggested that due to structural similarity between toxins, a vaccine against Centruroides noxius could be efficient against other, more dangerous, Centruroides species that cause more public health problems. [19]  

Related Research Articles

<span class="mw-page-title-main">Slotoxin</span> Chemical compound

Slotoxin is a peptide from Centruroides noxius Hoffmann scorpion venom. It belongs to the short scorpion toxin superfamily.

<span class="mw-page-title-main">Margatoxin</span>

Margatoxin (MgTX) is a peptide that selectively inhibits Kv1.3 voltage-dependent potassium channels. It is found in the venom of Centruroides margaritatus, also known as the Central American Bark Scorpion. Margatoxin was first discovered in 1993. It was purified from scorpion venom and its amino acid sequence was determined.

Tamapin is a toxin from the Indian Red Scorpion, which is a selective and potent blocker of SK2 channels.

<span class="mw-page-title-main">Cobatoxin</span> Chemical compound

Cobatoxin is a toxin present in the venom of the scorpion Centruroides noxius. It blocks two potassium channel subtypes; voltage-gated and calcium-activated channels.

Hanatoxin is a toxin found in the venom of the Grammostola spatulata tarantula. The toxin is mostly known for inhibiting the activation of voltage-gated potassium channels, most specifically Kv4.2 and Kv2.1, by raising its activation threshold.

Centruroides baergi is a species of scorpion in the family Buthidae. They are commonly found in highlands and are almost exclusively found in the states of Oaxaca and southern Puebla, Mexico. C. baergi is the most abundant scorpion of the genus in the state of Oaxaca, making up a third of Centruroides reported between 2008 and 2014.

Anuroctoxin is a peptide from the venom of the Mexican scorpion Anuroctonus phaiodactylus. This neurotoxin belongs to the alpha family of potassium channel acting peptides. It is a high-affinity blocker of Kv1.3 channels.

Butantoxin (BuTX) is a compound of the venom of three Brazilian and an Argentinean scorpion species of the genus Tityus. Butantoxin reversibly blocks the voltage-gated K+ channels Shaker B and Kv1.2, and the Ca2+-activated K+ channelsKCa 1.1 and KCa 3.1.

Ergtoxin is a toxin from the venom of the Mexican scorpion Centruroides noxius. This toxin targets hERG potassium channels.

<span class="mw-page-title-main">Pandinus imperator (Pi3) toxin</span>

Pi3 toxin is a purified peptide derivative of the Pandinus imperator scorpion venom. It is a potent blocker of voltage-gated potassium channel, Kv1.3 and is closely related to another peptide found in the venom, Pi2.

<span class="mw-page-title-main">Cll1</span> Scorpion protein

Toxin Cll1 is a toxin from the venom of the Mexican scorpion Centruroides limpidus limpidus, which changes the activation threshold of sodium channels by binding to neurotoxin binding site 4, resulting in increased excitability.

Centruroides suffusus suffusus toxin II (CssII) is a scorpion β-toxin from the venom of the scorpion Centruroides suffusus suffusus. CssII primarily affects voltage-gated sodium channels by causing a hyperpolarizing shift of voltage dependence, a reduction in peak transient current, and the occurrence of resurgent currents.

HgeTx1 (systematic name: α-KTx 6.14) is a toxin produced by the Mexican scorpion Hoffmanihadrurus gertschi that is a reversible blocker of the Shaker B K+-channel, a type of voltage-gated potassium channels.

Pi4 is a short toxin from the scorpion Pandinus imperator that blocks specific potassium channels.

Beta-mammal toxin Cn2, also known as Cn2 toxin, is a single chain β-scorpion neurotoxic peptide and the primary toxin in the venom of the Centruroides noxius Hoffmann scorpion. The toxin specifically targets mammalian Nav1.6 voltage-gated sodium channels (VGSC).

Beta-toxin Cll2, shortened to Cll2, is a toxin in the venom of the Mexican Scorpion species Centruroides limpidus limpidus. The toxin belongs to the β-class family of sodium channel-inhibiting scorpion toxins. It affects voltage-dependent activation, conductance and resurgent currents of voltage gated sodium channels by binding to site 4.

Intrepicalcin (ViCaTx1) is a short peptide toxin found in the venom of scorpion Vaejovis intrepidus. It is one of a group of short, basic peptides called calcins, which bind to ryanodine receptors (RyRs) and thereby trigger calcium release from the sarcoplasmic reticulum.

Centruroides noxius is a species of scorpion native to Mexico.

<span class="mw-page-title-main">Tst26</span>

The Tst26 toxin is a voltage-gated potassium channel blocker present in the venom of Tityus stigmurus, a species of Brazilian scorpion. Tst26 selectively blocks Kv1.2 and Kv1.3 channels.

The CmERG1 toxin is a peptide composed of 42 amino acids, found in venom from the Colombian scorpion Centruroides margaritatus. It blocks human ether-a-go-go-Related gene (hERG) potassium channels, which are important for cardiac action potential repolarization.

References

  1. 1 2 3 4 "Kalium: Scorpion Toxins Active on Potassium Channels". kaliumdb.org. Retrieved 2017-10-09.
  2. 1 2 3 4 5 Possani, Lourival Domingos; Martin, Brian M.; Svendsen, I. B. (1982-09-01). "The primary structure of noxiustoxin: A K+ channel blocking peptide, purified from the venom of the scorpion Centruroides noxius Hoffmann". Carlsberg Research Communications. 47 (5): 285–289. doi: 10.1007/bf02907789 . ISSN   0105-1938.
  3. 1 2 "Noxiustoxin | #STN-340 | Alomone labs". www.alomone.com. Retrieved 2017-10-09.
  4. ↑ Dauplais, M.; Gilquin, B.; Possani, L. D.; Gurrola-Briones, G.; Roumestand, C.; Menez, A. (1995). "Determination of the three-dimensional solution structure of noxiustoxin: analysis of structural differences with related short-chain scorpion toxins". Biochemistry. 34 (51): 16563–16573. doi:10.2210/pdb1sxm/pdb. PMID   8527429.
  5. ↑ "Potassium channel toxin alpha-KTx 2.1 - Centruroides noxius (Mexican scorpion)". www.uniprot.org. Retrieved 2017-10-09.
  6. 1 2 Possani, Lourival D; Corona, Miguel; Zurita, Mario; Rodrı́guez, Mario H (2002). "From Noxiustoxin to Scorpine and Possible Transgenic Mosquitoes Resistant to Malaria". Archives of Medical Research. 33 (4): 398–404. doi:10.1016/s0188-4409(02)00370-3. PMID   12234530.
  7. ↑ Possani, Lourival D; Zurita, Mario; Delepierre, Muriel; Hernández, Fidel H; Rodrguez, Mario H (1998). "From Noxiustoxin to Shiva-3, a peptide toxic to the sporogonic development of Plasmodium berghei". Toxicon. 36 (11): 1683–1692. doi:10.1016/s0041-0101(98)00161-5. PMID   9792185.
  8. ↑ Jover, E.; Couraud, F.; Rochat, H. (1980-08-29). "Two types of scorpion neurotoxins characterized by their binding to two separate receptor sites on rat brain synaptosomes". Biochemical and Biophysical Research Communications. 95 (4): 1607–1614. doi:10.1016/S0006-291X(80)80082-9. ISSN   0006-291X. PMID   7417336.
  9. 1 2 3 Carbone, Emilio; Wanke, Enzo; Prestipino, Gianfranco; Possani, Lourival D.; Maelicke, Alfred (1982-03-04). "Selective blockage of voltage-dependent K+ channels by a novel scorpion toxin". Nature. 296 (5852): 90–91. Bibcode:1982Natur.296...90C. doi:10.1038/296090a0. PMID   6278313. S2CID   32258371.
  10. 1 2 Drakopoulou, E.; Cotton, J.; Virelizier, H.; Bernardi, E.; Schoofs, A.R.; Partiseti, M.; Choquet, D.; Gurrola, G.; Possani, L.D. (1995). "Chemical Synthesis, Structural and Functional Characterization of Noxiustoxin, a Powerful Blocker of Lymphocyte Voltage-Dependent K+ Channels". Biochemical and Biophysical Research Communications. 213 (3): 901–907. doi:10.1006/bbrc.1995.2214. PMID   7654252.
  11. ↑ Dauplais, Marc; Gilquin, Bernard; Possani, Lourival D.; Gurrola-Briones, Georgina; Roumestand, Christian; Menez, Andre (1995-12-01). "Determination of the Three-Dimensional Solution Structure of Noxiustoxin: Analysis of Structural Differences with Related Short-Chain Scorpion Toxins". Biochemistry. 34 (51): 16563–16573. doi:10.1021/bi00051a004. ISSN   0006-2960. PMID   8527429.
  12. ↑ Valdivia, Hector H.; Smith, Jeffrey S.; Martin, Brian M.; Coronado, Roberto; Possani, Lourival D. (1988-01-04). "Charybdotoxin and noxiustoxin, two homologous peptide inhibitors of the K+(Ca2+) channel". FEBS Letters. 226 (2): 280–284. doi: 10.1016/0014-5793(88)81439-x . ISSN   1873-3468. PMID   2448164.
  13. ↑ Sitges, M.; Possani, L. D.; Bayón, A. (June 1986). "Noxiustoxin, a short-chain toxin from the Mexican scorpion Centruroides noxius, induces transmitter release by blocking K+ permeability". The Journal of Neuroscience. 6 (6): 1570–1574. doi: 10.1523/JNEUROSCI.06-06-01570.1986 . ISSN   0270-6474. PMC   6568734 . PMID   3012016.
  14. 1 2 Gurrola, G. B.; Molinar-Rode, R.; Sitges, M.; Bayon, A.; Possani, L. D. (1989). "Synthetic peptides corresponding to the sequence of noxiustoxin indicate that the active site of this K+ channel blocker is located on its amino-terminal portion". Journal of Neural Transmission. 77 (1): 11–20. doi:10.1007/BF01255815. PMID   2746197. S2CID   41665121.
  15. 1 2 Carbone, E.; Prestipino, G.; Spadavecchia, L.; Franciolini, F.; Possani, L. D. (May 1987). "Blocking of the squid axon K+ channel by noxiustoxin: a toxin from the venom of the scorpion Centruroides noxius". Pflügers Archiv: European Journal of Physiology. 408 (5): 423–431. doi:10.1007/BF00585064. ISSN   0031-6768. PMID   2439979. S2CID   20992757.
  16. ↑ Possani, Lourival Domingos; Dent, Myrna A. R.; Martin, Brian M.; Maelicke, Alfred; Svendsen, Ib (1981-07-01). "The amino terminal sequence of several toxins from the venom of the Mexican scorpion Centruroides noxius Hoffmann". Carlsberg Research Communications. 46 (4): 207. doi: 10.1007/bf02906498 . ISSN   0105-1938.
  17. ↑ Dent, Myrna A.R.; Possani, Lourival D.; Ramírez, Guillermo A.; Fletcher, Paul L. (1980). "Purification and characterization of two mammalian toxins from the venom of the Mexican scorpion Centruroides noxius Hoffmann". Toxicon. 18 (3): 343–350. doi:10.1016/0041-0101(80)90015-x. PMID   7394823.
  18. ↑ Dehesa-Dávila, Manuel; Ramfrez, Angelina N; Zamudio, Fernando Z; Gurrola-Briones, Georgina; Liévano, Arturo; Darszon, Alberto; Possani, Lourival D (1996). "Structural and functional comparison of toxins from the venom of the scorpions Centruroides infamatus infamatus, centruroides limpidus limpidus and Centruroides noxius". Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology. 113 (2): 331–339. doi:10.1016/0305-0491(95)02031-4. PMID   8653586.
  19. ↑ Hernández, Ricardo; Gazarian, Tatiana G; Hérion, Pascal S; Gazarian, Karlen G (2002). "Molecular localization and crossreactivity of two epitopes of noxiustoxin from scorpion Centruroides noxius, identified by a panel of monoclonal antibodies and peptide mimotopes". Immunology Letters. 80 (2): 97–103. doi:10.1016/s0165-2478(01)00320-0. PMID   11750040.
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